Abstract
Busulfan (BU) is widely used in conditioning regimens prior to hematopoietic stem cell transplantation (HSCT). The exposure-escalated BU directed by therapeutic drug monitoring (TDM) is extremely necessary for the patients with high-risk hematologic malignancies in order to diminish relapse, but it increases the risk of drug-induced toxicity. BU exposure, involved in the glutathione- (GSH-) glutathione S-transferases (GSTs) pathway and proinflammatory response, is associated with clinical outcomes after HSCT. However, the expression of genes in the GSH-GSTs pathway is regulated by NF-E2-related factor 2 (Nrf2) that can also alleviate inflammation. In this study, we evaluated the influence of NRF2 polymorphisms on BU exposure, proinflammatory cytokine levels, and clinical outcomes in HSCT patients. A total of 87 Chinese adult patients receiving twice-daily intravenous BU were enrolled. Compared with the patients carrying wild genotypes, those with NRF2 -617 CA/AA genotypes showed higher plasma interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF)-α levels, poorer overall survival (OS; RR = 3.91), and increased transplant-related mortality (TRM; HR = 4.17). High BU exposure [area under the concentration-time curve (AUC) > 9.27 mg/L × h)] was related to BU toxicities. Furthermore, NRF2 -617 CA/AA genotypes could significantly impact TRM (HR = 4.04; p = 0.0142) and OS (HR = 3.69; p = 0.0272) in the patients with high BU AUC. In vitro, we found that high exposure of endothelial cell (EC) to BU, in the absence of Nrf2, elicited the hyperstimulation of NF-κB-p65, accompanied with the elevated secretion of proinflammatory cytokines, and led to EC death. These results showed that NRF2 -617 CA/AA genotypes, correlated with high proinflammatory cytokine levels, could predict inferior outcomes in HSCT patients with high BU AUC. Thus, NRF2 -617 CA/AA genotyping combined with TDM would further optimize personalized BU dosing for sufficient efficacy and safety endpoint.
Highlights
The bifunctional alkylating agent busulfan (1, 4-butanediol dimethanesulfonate; BU) is widely used as a major component of conditioning regimens prior to hematopoietic stem cell transplantation (HSCT) (Bredeson et al, 2013)
We evaluated the influence of NRF2 polymorphisms on BU exposure, proinflammatory cytokine levels, and clinical outcomes in HSCT patients
These results showed that NRF2 -617 CA/AA genotypes, correlated with high proinflammatory cytokine levels, could predict inferior outcomes in HSCT patients with high BU area under the plasma concentrationtime curve (AUC)
Summary
The bifunctional alkylating agent busulfan (1, 4-butanediol dimethanesulfonate; BU) is widely used as a major component of conditioning regimens prior to hematopoietic stem cell transplantation (HSCT) (Bredeson et al, 2013). Personalized BU dosing, directed by therapeutic drug monitoring (TDM), can optimize the target BU exposure to improve clinical outcomes (Palmer et al, 2016). It is necessary for the patients with high-risk hematologic malignancies to achieve the target BU of 28.7 mg/L × h (daily dosing) in order to diminish relapse (Shea et al, 2015). Previous studies showed interindividual variability in BU exposure, which was associated with different blood glutathione (GSH) and glutathione S-transferases (GSTs) such as GSTA1 and GSTA2 (Almog et al, 2011; Bonifazi et al, 2014; Yin et al, 2015). BU is metabolized mainly in liver through GSTs, a family of phase II detoxification enzymes that catalyze the conjugation of GSH to various xenobiotics (Gibbs et al, 1996)
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